We have formed a successful collaborative research effort that has ascertained and evaluated affected and at-risk family members from 800 multiplex Parkinson disease (PD) families. These data allowed us to perform linkage analysis which identified a region on chromosome 2q which is linked to disease in the subset of families with the strongest family history of PD. We have completed the first genomewide association study (GWAS) in familial PD, which detected association to two genes previously implicated in PD (SNCA and MAPT), and which also detected association to several novel genes, including GAK/DGKQ. We have also performed extensive studies in our unique familial sample to test and characterize genes implicated in PD and identified novel mutations in LRRK2 and parkin. We were the first to demonstrate that haploinsufficiency of a parkin dosage mutation (duplications or deletions) increases the risk of PD, while a single sequence mutation does not. Results from our complementary linkage and GWAS analyses form the basis of the work proposed for the next 5 years. We will move this study beyond linkage and association to the identification of novel genes and DNA variants that underlie an increased risk for PD. Our focus will be on the identification of both rare and common variants contributing to PD susceptibility. Utilizing innovative genomic and bioinformatic approaches not previously applied in PD, we will identify the most promising candidate genes for PD susceptibility and perform molecular studies at both the DNA and RNA level to identify all sequence variants and then rigorously evaluate the role of altered gene expression as a possible mechanism contributing to disease susceptibility. Our unique familial PD resource provides the ideal sample in which to perform these studies. Importantly, our successful brain tissue repository enables us to perform key molecular studies in the tissue of the same individual in which the variant or mutation was initially identified. We will complete the following specific aims: 1) Identify the gene(s) on chromosome 2q that contributes to PD susceptibility. 2) Direct the PD GWAS Consortium and identify novel candidate genes for PD susceptibility and age of onset. 3) Expand the existing patient resources collecting more extensive data and biological samples to increase the power to identify and delineate PD susceptibility genes.